Therapeutic agent preparations into a lumen of the intestinal tract using a swallowable drug delivery device

ABSTRACT

Embodiments of the invention provide swallowable devices, preparations and methods for delivering drugs and other therapeutic agents within the GI tract. Many embodiments provide a swallowable device for delivering the agents. Particular embodiments provide a swallowable device such as a capsule for delivering drugs into the intestinal wall or other GI lumen. Embodiments also provide various drug preparations that are configured to be contained within the capsule, advanced from the capsule into the intestinal wall and degrade within the wall to release the drug to produce a therapeutic effect. The preparation can be coupled to an actuator having a first configuration where the preparation is contained in the capsule and a second configuration where the preparation is advanced out of the capsule into the intestinal wall. Embodiments of the invention are particularly useful for the delivery of drugs which are poorly absorbed, tolerated and/or degraded within the GI tract.

CROSS-REFERENCES TO RELATED APPLICATIONS

This application is a continuation of U.S. patent application Ser. No.15/668,421 (Attorney Docket No. 45126-705.402), filed Aug. 3, 2017, nowU.S. patent Ser. No. ______, which is a divisional of U.S. patentapplication Ser. No. 14/282,864 (Attorney Docket No. 42197-705.401),filed May 20, 2014, now U.S. Pat. No. 9,757,548, which is a divisionalof U.S. patent application Ser. No. 12/978,164 (Attorney Docket No.42197-705.201), filed Dec. 23, 2010, now U.S. Pat. No. 8,759,284, whichclaims the benefit of priority to U.S. Application Ser. Nos. 61/339,941filed Mar. 10, 2010, (Attorney Docket No. 42197-705.101) entitled,“Swallowable Drug Delivery Device and Methods of Delivery”, 61/284,766,filed Dec. 24, 2009, (Attorney Docket No. 42197-704.101) entitled,“Swallowable Drug Delivery Device and Methods of Drug Delivery”,61/340,331, filed Mar. 15, 2010, (Attorney Docket No. 42197-706.101)entitled” Swallowable Drug Delivery Device and Methods of Delivery“; and61/395,304, filed May 10, 2010, (Attorney Docket No. 42197-707.101)entitled, Swallowable Drug Delivery Device and Method of Delivery” whichare fully incorporated by reference herein for all purposes.

This application is also related to U.S. application Ser. No.12/978,301, filed Dec. 23, 2010, (Attorney Docket No. 42197-707.201)entitled “Swallowable Drug Delivery Device and Method of Delivery”; andSer. No. 12/978,233, filed Dec. 23, 2010, (Attorney Docket No.42197-704.201) entitled, “Swallowable Drug Delivery Device and Methodsof Drug Delivery”; all of which are fully incorporated by referenceherein for all purposes.

BACKGROUND OF THE INVENTION

Field of the Invention

Embodiments of the invention relate to swallowable drug deliverydevices. More specifically, embodiments of the invention relate toswallowable drug delivery devices for delivering drugs to the smallintestine.

While there has been an increasing development of new drugs in recentyears for the treatment of a variety of diseases, many have limitedapplication because they cannot be given orally. This is due to a numberof reasons including: poor oral toleration with complications includinggastric irritation and bleeding; breakdown/degradation of the drugcompounds in the stomach; and poor, slow or erratic absorption of thedrug. Conventional alternative drug delivery methods such as intravenousand intramuscular delivery have a number of drawbacks including pain andrisk of infection from a needle stick, requirements for the use ofsterile technique and the requirement and associated risks ofmaintaining an IV line in a patient for an extended period of time.While other drug delivery approaches have been employed such asimplantable drug delivery pumps, these approaches require thesemi-permanent implantation of a device and can still have many of thelimitations of IV delivery. Thus, there is a need for an improved methodfor delivery of drugs and other therapeutic agents.

BRIEF SUMMARY OF THE INVENTION

Embodiments of the invention provide devices, systems, kits and methodsfor delivering drugs and other therapeutic agents to various locationsin the body. Many embodiments provide a swallowable device fordelivering drugs and other therapeutic agents within theGastrointestinal (GI) tract. Particular embodiments provide aswallowable device such as a capsule for delivering drugs and othertherapeutic agents into the wall of the small intestine or other GIorgan wall. Embodiments of the invention are particularly useful for thedelivery of drugs and other therapeutic agents which are poorlyabsorbed, poorly tolerated and/or degraded within the GI tract. Further,embodiments of the invention can be used to deliver drugs which werepreviously only capable of or preferably delivered by intravenous orother form of parenteral administration (e.g., intramuscular, etc).

In one embodiment, a therapeutic agent preparation for delivery into alumen wall of the intestinal tract, the preparation comprises atherapeutically effective dose of at least one therapeutic agent. Thepreparation has a shape and material consistency to be contained in aswallowable capsule and delivered from the capsule into the lumen wallto release the dose of therapeutic agent from within the lumen wall.

In another embodiment, a therapeutic agent preparation for delivery intoa lumen wall of the intestinal tract, the preparation comprises atherapeutically effective dose of at least one therapeutic agent. Thepreparation is configured to be contained in a swallowable capsule andoperably coupled to an actuator having a first configuration and asecond configuration. The preparation is contained within the capsule inthe first configuration and advanced out of the capsule and into thelumen wall in the second configuration to deliver the therapeutic agentinto the lumen wall.

In yet another embodiment, a method for delivering a therapeutic agentinto the wall of the small intestine comprises swallowing a drugdelivery device comprising a capsule, an actuator and an embodiment ofthe therapeutic agent preparation. The actuator responsive to acondition in the small intestine is actuated to deliver the therapeuticagent preparation into the wall of the small intestine.

In one aspect, the invention provides a swallowable device fordelivering drugs or other therapeutic agent into the wall of the smallor large intestine. The device comprises a capsule sized to be swallowedand pass through the intestinal tract. The capsule includes an interiorvolume and can be fabricated from various biocompatible polymers knownin the art including various biodegradable polymers. The capsuleincludes at least one guide tube, one or more tissue penetrating memberspositioned in the at least one guide tube, a delivery member and anactuating mechanism. The tissue penetrating member will typicallycomprise a hollow needle or other like structure and will have a lumenand a tissue penetrating end for penetrating a selectable depth into theintestinal wall. In various embodiments, the device can include a secondand a third tissue penetrating member with additional numberscontemplated. Each tissue penetrating member can include the same or adifferent drug. In preferred embodiments having multiple tissuepenetrating members, the tissue penetrating members can be symmetricallydistributed around the perimeter of the capsule so as to anchor thecapsule onto the intestinal wall during delivery of drug. In someembodiments, all or a portion of the tissue penetrating member (e.g.,the tissue penetrating end) can be fabricated from the drug itself. Inthese and related embodiments, the drug can have a needle or dart-likestructure (with or without barbs) configured to penetrate and beretained in the intestinal wall.

The tissue penetrating member can be fabricated from variousbiodegradable materials (e.g., PGLA) so as to degrade within the smallintestine and thus provide a fail-safe mechanism for detaching thetissue penetrating member from the intestinal wall should this componentbecome retained in the intestinal wall. Additionally, in theses andrelated embodiments, selectable portions of the capsule can befabricated from such biodegradable materials so as to allow the entiredevice to controllably degrade into smaller pieces. Such embodimentsfacilitate passage and excretion of the devices through GI tract. Inparticular embodiments, the capsule can include seams of biodegradablematerial which controllably degrade to produce capsule pieces of aselectable size and shape to facilitate passage through the GI tract.The seams can be pre-stressed, perforated or otherwise treated toaccelerate degradation. The concept of using biodegradable seams toproduce controlled degradation of a swallowable device in the GI tractcan also be applied to other swallowable devices such as swallowablecameras to facilitate passage through the GI tract and reduce thelikelihood of a device becoming stuck in the GI tract.

The delivery member is configured to advance the drug from the capsulethrough the tissue penetrating member lumen and into the intestinalwall. Typically, at least a portion of the delivery member isadvanceable within the tissue penetrating member lumen. The deliverymember can have a piston or like structure sized to fit within thedelivery member lumen. The distal end of the delivery member (the endwhich is advanced into tissue) can have a plunger element which advancesthe drug within tissue penetrating member lumen and also forms a sealwith the lumen. The plunger element can be integral or attached to thedelivery member. Preferably, the delivery member is configured to travela fixed distance within the needle lumen so as to deliver a fixed ormetered dose of drug into the intestinal wall. This can be achieved byone or more of the selection of the diameter of the delivery member(e.g., the diameter can be distally tapered), the diameter of the tissuepenetrating member (which can be narrowed at its distal end), use of astop, and/or the actuating mechanism. For embodiments of the devicehaving a tissue penetrating member fabricated from drug (e.g., a drugdart), the delivery member is adapted to advance the dart out of thecapsule and into tissue.

The delivery member and tissue penetrating member can be configured forthe delivery of liquid, semi-liquid or solid forms of drug or all three.Solid forms of drug can include both powder or pellet. Semi liquid caninclude a slurry or paste. The drug can be contained within a cavity ofthe capsule, or in the case of the liquid or semi-liquid, within anenclosed reservoir. In some embodiments, the capsule can include a firstsecond, or a third drug (or more). Such drugs can be contained withinthe tissue penetrating member lumen (in the case of solids or powder) orin separate reservoirs within the capsule body.

The actuating mechanism can be coupled to at least one of the tissuepenetrating member or the delivery member. The actuating mechanism isconfigured to advance the tissue penetrating member a selectabledistance into the intestinal wall as well as advance the delivery memberto deliver the drug and then withdraw the tissue penetrating member fromthe intestinal wall. In various embodiments, the actuating mechanism cancomprise a preloaded spring mechanism which is configured to be releasedby the release element. Suitable springs can include both coil(including conical shaped springs) and leaf springs with other springstructures also contemplated. In particular embodiments, the spring canbe cone shaped to reduce the length of the spring in the compressedstate even to the point where the compressed length of the spring isabout the thickness of several coils (e.g., two or three) or only onecoil.

In particular embodiments the actuating mechanism comprises a spring, afirst motion converter, and a second motion converter and a trackmember. The release element is coupled to the spring to retain thespring in a compressed state such that degradation of the releaseelement releases the spring. The first motion converter is configured toconvert motion of the spring to advance and withdraw the tissuepenetrating element in and out of tissue. The second motion converter isconfigured to convert motion of the spring to advance the deliverymember into the tissue penetrating member lumen. The motion convertersare pushed by the spring and ride along a rod or other track memberwhich serves to guide the path of the converters. They engage the tissuepenetrating member and/or delivery member (directly or indirectly) toproduce the desired motion. They are desirably configured to convertmotion of the spring along its longitudinal axis into orthogonal motionof the tissue penetrating member and/or delivery member thoughconversion in other directions is also contemplated. The motionconverters can have a wedge, trapezoidal or curved shape with othershapes also contemplated. In particular embodiments, the first motionconverter can have a trapezoidal shape and include a slot which engagesa pin on the tissue penetrating member that rides in the slot. The slotcan have a trapezoidal shape that mirrors or otherwise corresponds tothe overall shape of the converter and serves to push the tissuepenetrating member during the upslope portion of the trapezoid and thenpull it back during the down slope portion. In one variation, one orboth of the motion converters can comprise a cam or cam like devicewhich is turned by the spring and engages the tissue penetrating and/ordelivery member.

In other variations, the actuating mechanism can also comprise anelectro-mechanical device/mechanism such as a solenoid, or apiezoelectric device. In one embodiment, the piezoelectric device cancomprise a shaped piezoelectric element which has a non-deployed anddeployed state. This element can be configured to go into the deployedstate upon the application of a voltage and then return to thenon-deployed state upon the removal of the voltage. This and relatedembodiments allow for a reciprocating motion of the actuating mechanismso as to both advance the tissue penetrating member and then withdrawit.

The release element is coupled to at least one of the actuatingmechanism or a spring coupled to the actuating mechanism. In particularembodiments, the release element is coupled to a spring positionedwithin the capsule so as to retain the spring in a compressed state.Degradation of the release element releases the spring to actuate theactuation mechanism. In many embodiments, the release element comprisesa material configured to degrade upon exposure to chemical conditions inthe small or large intestine such as pH. Typically, the release elementis configured to degrade upon exposure to a selected pH in the smallintestine, e.g., 7.0, 7.1, 7.2, 7.3, 7.4, 8.0 or greater. However, itcan also be configured to degrade in response to other conditions in thesmall intestine. In particular embodiments, the release element can beconfigured to degrade in response to particular chemical conditions inthe fluids in the small intestine such as those which occur afteringestion of a meal (e.g., a meal high in fats or proteins).

Biodegradation of the release element from one or more conditions in thesmall intestine (or other location in the GI tract) can be achieved byselection of the materials for the release element, the amount of crosslinking of those materials as well as the thickness and other dimensionsof the release elements. Lesser amounts of cross linking and or thinnerdimensions can increase the rate of degradation and visa versa. Suitablematerials for the release element can comprise biodegradable materialssuch as various enteric materials which are configured to degrade uponexposure to the higher pH or other condition in the small intestine. Theenteric materials can be copolymerized or otherwise mixed with one ormore polymers to obtain a number of particular material properties inaddition to biodegradation. Such properties can include withoutlimitation stiffness, strength, flexibility and hardness.

In particular embodiments, the release element can comprise a film orplug that fits over or otherwise blocks the guide tube and retains thetissue penetrating member inside the guide tube. In these and relatedembodiments, the tissue penetrating member is coupled to a spring loadedactuating mechanism such that when the release element is degradedsufficiently, it releases the tissue penetrating member which thensprings out of the guide tube to penetrate into the intestinal wall. Inother embodiments, the release element can be shaped to function as alatch which holds the tissue penetrating element in place. In these andrelated embodiments, the release element can be located on the exterioror the interior of the capsule. In the interior embodiments, the capsuleand guide tubes are configured to allow for the ingress of intestinalfluids into the capsule interior to allow for the degradation of therelease element.

In some embodiments, the actuating mechanism can be actuated by means ofa sensor, such as a pH or other chemical sensor which detects thepresence of the capsule in the small intestine and sends a signal to theactuating mechanism (or to an electronic controller coupled to theactuating mechanism to actuate the mechanism). Embodiments of a pHsensor can comprise an electrode-based sensor or it can be amechanically-based sensor such as a polymer which shrinks or expandsupon exposure to the pH or other chemical conditions in the smallintestine. In related embodiments, an expandable/contractable sensor canalso comprise the actuating mechanism itself by using the mechanicalmotion from the expansion or contraction of the sensor.

According to another embodiment for detecting that the device is in thesmall intestine (or other location in the GI tract), the sensor cancomprise a strain gauge or other pressure/force sensor for detecting thenumber of peristaltic contractions that the capsule is being subject towithin a particular location in the intestinal tract. In theseembodiments, the capsule is desirably sized to be gripped by the smallintestine during a peristaltic contraction). Different locations withinthe GI tract have different number of peristaltic contractions. Thesmall intestine has between 12 to 9 contractions per minute with thefrequency decreasing down the length of the intestine. Thus, accordingto one or more embodiments detection of the number of peristalticcontractions can be used to not only determine if the capsule is in thesmall intestine but the relative location within the intestine as well.

As an alternative or supplement to internally activated drug delivery,in some embodiments, the user may externally activate the actuatingmechanism to deliver drug by means of RF, magnetic or other wirelesssignaling means known in the art. In these and related embodiments, theuser can use a handheld device (e.g., a hand held RF device) which notonly includes signaling means, but also means for informing the userwhen the device is in the small intestine or other location in the GItract. The later embodiment can be implemented by including an RFtransmitter on the swallowable device to signal to the user when thedevice is in the small intestine or other location (e.g., by signalingan input from the sensor). The same handheld device can also beconfigured to alter the user when the actuating mechanism has beenactivated and the selected drug(s) delivered. In this way, the user isprovided confirmation that the drug has been delivered. This allows theuser to take other appropriate drugs/therapeutic agents as well as makeother related decisions (e.g., for diabetics to eat a meal or not andwhat foods should be eaten). The handheld device can also be configuredto send a signal to the swallowable device to over-ride the actuatingmechanism and so prevent, delay or accelerate the delivery of drug. Inuse, such embodiments allow the user to intervene to prevent, delay oraccelerate the delivery of drug based upon other symptoms and/or patientactions (e.g., eating a meal, deciding to go to sleep, exercise etc).

The user may also externally activate the actuating mechanism at aselected time period after swallowing the capsule. The time period canbe correlated to a typical transit time or range of transit times forfood moving through the user's GI tract to a particular location in thetract such as the small intestine.

Another aspect of the inventions provides therapeutic agent preparationsfor delivery into the wall of the small intestine (or other wall of alumen in the intestinal tract) using embodiments of the swallowabledevice described herein. The preparation comprises a therapeuticallyeffective dose of at least one therapeutic agent (e.g., insulin, ananti-seizure compound, non-steroidal anti-inflammatory drugs, anantibiotic etc). It may comprise a solid, liquid or combination of bothand can include one or more pharmaceutical excipients. The preparationhas a shape and material consistency to be contained in embodiments ofthe swallowable capsule, delivered from the capsule into the lumen walland degrade within the lumen wall to release the dose of therapeuticagent. The preparation may also have a selectable surface area to volumeratio so as enhance or otherwise control the rate of degradation of thepreparation in the wall of the small intestine or other body lumen. Invarious embodiments, the preparation can be configured to be coupled toan actuator such as a release element or actuation mechanism which has afirst configuration in which the preparation is contained in the capsuleand a second configuration in which the preparation is advanced out ofthe capsule and into the wall of the small intestine. The dose of thedrug or other therapeutic agent in the preparation can be titrateddownward from that which would be required for conventional oraldelivery methods so that potential side effects from the drug can bereduced.

Typically, though not necessarily, the preparation will be shaped andotherwise configured to be contained in the lumen of a tissuepenetrating member, such as a hollow needle which is configured to beadvanced out of the capsule and into the wall of the small intestine.The preparation itself may comprise a tissue penetrating memberconfigured to be advanced into the wall of the small intestine or otherlumen in the intestinal tract.

Another aspect of the invention provides methods for the delivery ofdrugs and the therapeutic agents into the walls of the GI tract usingembodiments of the swallowable drug delivery devices. Such methods canbe used for the delivery of therapeutically effective amounts of avariety of drugs and other therapeutic agents. These include a number oflarge molecule peptides and proteins which would otherwise requireinjection due to chemical breakdown in the stomach e.g., growth hormone,parathyroid hormone, insulin, interferons and other like compounds.Suitable drugs and other therapeutic agents which can be delivered byembodiments of invention include various chemotherapeutic agents (e.g.,interferon), antibiotics, antivirals, insulin and related compounds,glucagon like peptides (e.g., GLP-1, exenatide), parathyroid hormones,growth hormones (e.g., IFG and other growth factors), anti-seizureagents, immune suppression agents and anti-parasitic agents such asvarious anti-malarial agents. The dosage of the particular drug can betitrated for the patient's weight, age, condition or other parameter.

In various method embodiments, embodiments of the drug swallowable drugdelivery device can be used to deliver a plurality of drugs for thetreatment of multiple conditions or for the treatment of a particularcondition (e.g., a mixture of protease inhibitors for treatment HIVAIDS). In use, such embodiments allow a patient to forgo the necessityof having to take multiple medications for a particular condition orconditions. Also, they provide a means for facilitating that a regimenof two or more drugs is delivered and absorbed into the small intestineand thus, the blood stream at about the same time. Due to differences inchemical makeup, molecular weight, etc, drugs can be absorbed throughthe intestinal wall at different rates, resulting in differentpharmacokinetic distribution curves. Embodiments of the inventionaddress this issue by injecting the desired drug mixtures at about thesame time. This in turn improves pharmacokinetics and thus, the efficacyof the selected mixture of drugs.

Further details of these and other embodiments and aspects of theinvention are described more fully below, with reference to the attacheddrawing figures.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1a is a lateral viewing showing an embodiment of a swallowable drugdelivery device.

FIG. 1b is a lateral viewing showing an embodiment of a system includinga swallowable drug delivery device.

FIG. 1c is a lateral viewing showing an embodiment of a kit including aswallowable drug delivery device and a set of instructions for use.

FIG. 1d is a lateral viewing showing an embodiment of a swallowable drugdelivery device including a drug reservoir.

FIG. 2 is a lateral view illustrating an embodiment of the swallowabledrug delivery device having a spring loaded actuation mechanism foradvancing tissue penetrating members into tissue.

FIG. 3 is a lateral view illustrating an embodiment of the swallowabledrug delivery device having a spring loaded actuation mechanism having afirst motion converter.

FIG. 4 is a lateral view illustrating an embodiment of the swallowabledrug delivery device having a spring loaded actuation mechanism havingfirst and a second motion converter.

FIG. 5 is a perspective view illustrating engagement of the first andsecond motion converters with the tissue penetrating member and deliverymembers.

FIG. 6 is a cross sectional view illustrating an embodiment of theswallowable drug delivery device having a single tissue penetratingmember and an actuating mechanism for advancing the tissue penetratingmember.

FIG. 7a is a cross sectional view illustrating an embodiment of theswallowable drug delivery device having multiple tissue penetratingmembers and an actuating mechanism for advancing the tissue penetratingmembers.

FIG. 7b is a cross sectional view illustrating deployment of the tissuepenetrating members of the embodiment of FIG. 7a to deliver medicationto a delivery site and anchor the device in the intestinal wall duringdelivery.

FIGS. 8a-8c are side view illustrating positioning of the drug deliverydevice in the small intestine and deployment of the tissue penetratingmembers to deliver drug; FIG. 8a shows the device in the small intestineprior to deployment of the tissue penetrating members with the releaseelement in tact; FIG. 8b shows the device in the small intestine withthe release element degraded and the tissue penetrating elementsdeployed; and FIG. 8c shows the device in the small intestine with thetissue penetrating elements retracted and the drug delivered.

FIG. 9a shows an embodiment of a swallowable drug delivery deviceincluding a capsule having bio-degradable seams positioned to producecontrolled degradation of the capsule in the GI tract.

FIG. 9b shows the embodiment of FIG. 9a after having been degraded inthe GI tract into smaller pieces.

FIG. 10 shows an embodiment of a capsule having biodegradable seamsincluding pores and/or perforations to accelerate biodegradation of thecapsule.

FIG. 11 is a lateral viewing illustrating use of an embodiment of aswallowable drug delivery device including transit of device in the GItract and operation of the device to deliver drug.

DETAILED DESCRIPTION OF THE INVENTION

Embodiments of the invention provide devices, systems and methods fordelivering medications in to various locations in the body. As usedherein, the term “medication” refers to a medicinal preparation in anyform which can include drugs or other therapeutic agents as well as oneor more pharmaceutical excipients. Many embodiments provide aswallowable device for delivering medication within the GI tract.Particular embodiments provide a swallowable device such as a capsulefor delivering medications to the wall of the small intestine or otherGI organ.

Referring now to FIGS. 1-11, an embodiment of an device 10 for thedelivery of medication 100 to a delivery site DS in the intestinaltract, comprises a capsule 20 including at least one guide tube 30, oneor more tissue penetrating members 40 positioned or otherwiseadvanceable in the at least one guide tube, a delivery member 50, anactuating mechanism 60 and release element 70. Medication 100, alsodescribed herein as preparation 100, typically comprises at least onedrug or therapeutic agent 101 and may include one or more pharmaceuticalexcipients known in the art.

Device 10 can be configured for the delivery of liquid, semi-liquid orsolid forms of medication 100 or all three. Solid forms ofmedication/preparation 100 can include both powder or pellet. Semiliquid forms can include a slurry or paste. Whatever the form,preparation 100 desirably has a shape and material consistency allowingthe medication to be advanced out of the device, into the intestinalwall (or other luminal wall in the GI tract) and then degrade in theintestinal wall to release the drug or other therapeutic agent 101. Thematerial consistency can include one or more of the hardness, porosityand solubility of the preparation (in body fluids). The materialconsistency can be achieved by one or more of the following: i) thecompaction force used to make the preparation; ii) the use of one ormore pharmaceutical disintegrants known in the art; iii) use of otherpharmaceutical excipients; iv) the particle size and distribution of thepreparation (e.g., micronized particles); and v) use of micronizing andother particle formation methods known in the art. Suitable shapes forpreparation 100 can include cylindrical, cubical, rectangular, conical,spherical, hemispherical and combinations thereof. Also, the shape canbe selected so as to define a particular surface area and volume ofpreparation 100 and thus, the ratio between the two. The ratio ofsurface area to volume can in turn, be used to achieve a selected rateof degradation within the intestinal or other lumen wall. Larger ratios(e.g., larger amounts of surface area per unit volume) can be used toachieve faster rates of degradation and vice versa. In particularembodiments, the surface area to volume ratio can be in the range ofabout 1:1 to 100:1, with specific embodiments of 2:1, 5:1, 20:1, 25:1,50:1 and 75:1. Preparation/medication 100 will typically be pre-packedwithin a lumen 44 of tissue penetrating members 40, but can also becontained at another location within an interior 24 of capsule 20, or inthe case of a liquid or semi-liquid, within an enclosed reservoir 27.The medication can be pre-shaped to fit into the lumen or packed forexample, in a powder form. Typically, the device 10 will be configuredto deliver a single drug 101 as part of medication 100. However in someembodiments, the device 10 can be configured for delivery of multipledrugs 101 including a first second, or a third drug which can becompounded into a single or multiple medications 100. For embodimentshaving multiple medications/drugs, the medications can be contained inseparate tissue penetrating members 40 or within separate compartmentsor reservoirs 27 within capsule 20. In another embodiment, a first dose102 of medication 100 containing a first drug 101 can be packed into thepenetrating member(s) 40 and a second dose 103 of medication 100(containing the same or a different drug 101) can be coated onto thesurface 25 of capsule as is shown in the embodiment of FIG. 1b . Thedrugs 101 in the two doses of medication 102 and 103 can be the same ordifferent. In this way, a bimodal pharmacokinetic release of the same ordifferent drugs can be achieved. The second dose 103 of medication 100can have an enteric coating 104 to ensure that it is released in thesmall intestine and achieve a time release of the medication 100 aswell. Enteric coating 104 can include one or more enteric coatingsdescribed herein or known in the art.

A system 11 for delivery of medication 100 into the wall of the smallintestine or other location within the GI tract, may comprise device 10,containing one or more medications 100 for the treatment of a selectedcondition or conditions. In some embodiments, the system may include ahand held device 13, described herein for communicating with device 10as is shown in the embodiment of FIG. 1b . System 11 may also beconfigured as a kit 14 including system 11 and a set of instructions foruse 15 which are packaged in packaging 12 as is shown in the embodimentof FIG. 1c . The instructions can indicate to the patient when to takethe device 10 relative to one or more events such as the ingestion of ameal or a physiological measurement such as blood glucose, cholesterol,etc. In such embodiments, kit 14 can include multiple devices 10containing a regimen of medications 100 for a selected period ofadministration, e.g., a day, week, or multiple weeks depending upon thecondition to be treated.

Capsule 20 is sized to be swallowed and pass through the intestinaltract. The size can also be adjusted depending upon the amount of drugto be delivered as well as the patient's weight and adult vs. pediatricapplications. Capsule 20 includes an interior volume 24 and an outersurface 25 having one or more apertures 26 sized for guide tubes 30. Inaddition to the other components of device 10, (e.g., the actuationmechanism etc.) the interior volume can include one or more compartmentsor reservoirs 27. One or more portions of capsule 20 can be fabricatedfrom various biocompatible polymers known in the art, including variousbiodegradable polymers which in a preferred embodiment can comprise PGLA(polylactic-co-glycolic acid). Other suitable biodegradable materialsinclude various enteric materials described herein as well as lactide,glycolide, lactic acid, glycolic acid, para-dioxanone, caprolactone,trimethylene carbonate, caprolactone, blends and copolymers thereof. Asis described in further detail herein, in various embodiments, capsule20 can include seams 22 of bio-degradable material so as to controllablydegrade into smaller pieces 23 which are more easily passed through theintestinal tract. Additionally, in various embodiments, the capsule caninclude various radio-opaque or echogenic materials for location of thedevice using fluoroscopy, ultrasound or other medical imaging modality.In specific embodiments, all or a portion of the capsule can includeradio-opaque/echogenic markers 20 m as is shown in the embodiment ofFIGS. 1a and 1b . In use, such materials not only allow for the locationof device 10 in the GI tract, but also allow for the determination oftransit times of the device through the GI tract.

In preferred embodiments, tissue penetrating members 40 are positionedwithin guide tubes 30 which serve to guide and support the advancementof members 40 into tissue such as the wall of the small intestine orother portion of the GI tract. The tissue penetrating members 40 willtypically comprise a hollow needle or other like structure and will havea lumen 44 and a tissue penetrating end 45 for penetrating a selectabledepth into the intestinal wall IW. Member 40 may also include a pin 41for engagement with a motion converter 90 described herein. The depth ofpenetration can be controlled by the length of member 40, theconfiguration of motion converter 90 described herein as well as theplacement of a stop or flange 40 s on member 40 which can, in anembodiment, correspond to pin 41 described herein. Medication 100 willtypically be delivered into tissue through lumen 44. In manyembodiments, lumen 44 is pre-packed with the desired medication 100which is advanced out of the lumen using delivery member 50 or otheradvancement means (e.g. by means of force applied to a collapsibleembodiment of member 40). As an alternative, medication 100 can beadvanced into lumen 44 from another location/compartment in capsule 20.In some embodiments, all or a portion of the tissue penetrating member40 can be fabricated from medication 100 itself In these and relatedembodiments, the medication can have a needle or dart-like structure(with or without barbs) configured to penetrate and be retained in theintestinal wall, such as the wall of the small intestine. The dart canbe sized and shaped depending upon the medication, dose and desireddepth of penetration into the intestinal wall. Medication 100 can beformed into darts, pellets or other shapes using various compressionmolding methods known in the pharmaceutical arts.

In various embodiments, device 10 can include a second 42 and a third 43tissue penetrating member 40 as is shown in the embodiments of FIGS. 7aand 7b , with additional numbers contemplated. Each tissue penetratingmember 40 can be used to deliver the same or a different medication 100.In preferred embodiments, the tissue penetrating members 40 can besubstantially symmetrically distributed around the perimeter 21 ofcapsule 20 so as to anchor the capsule onto the intestinal wall IWduring delivery of medications 100. Anchoring capsule 20 in such a wayreduces the likelihood that the capsule will be displaced or moved byperistaltic contractions occurring during delivery of the medication. Inspecific embodiments, the amount of anchoring force can be adjusted tothe typical forces applied during peristaltic contraction of the smallintestine. Anchoring can be further facilitated by configured some orall of tissue penetrating members 40 to have a curved or arcuate shape.

Delivery member 50 is configured to advance medication 100 through thetissue penetrating member lumen 44 and into the intestinal wall IW.Accordingly, at least a portion of the delivery member 50 is advanceablewithin the tissue penetrating member lumen 44 and thus member 50 has asize and shape (e.g., a piston like shape) configured to fit within thedelivery member lumen 44.

In some embodiments, the distal end 50 d of the delivery member (the endwhich is advanced into tissue) can have a plunger element 51 whichadvances the medication within the tissue penetrating member lumen 44and also forms a seal with the lumen. Plunger element 51 can be integralor attached to delivery member 50. Preferably, delivery member 50 isconfigured to travel a fixed distance within the needle lumen 44 so asto deliver a fixed or metered dose of drug into the intestinal wall IW.This can be achieved by one or more of the selection of the diameter ofthe delivery member (e.g., the diameter can be distally tapered), thediameter of the tissue penetrating member (which can be narrowed at itsdistal end), use of a stop, and/or the actuating mechanism. However insome embodiments, the stroke or travel distance of member 50 can beadjusted in situ responsive to various factors such as one or moresensed conditions in the GI tract. In situ adjustment can be achievedthrough use of logic resource 29 (including controller 29 c) coupled toan electro-mechanical embodiment of actuating mechanism 60. This allowsfor a variable dose of medication and/or variation of the distance themedication is injected into the intestinal wall.

Actuating mechanism 60 can be coupled to at least one of the tissuepenetrating member 40 or delivery member 50. The actuating mechanism isconfigured to advance tissue penetrating member 40 a selectable distanceinto the intestinal wall IW as well as advance the delivery member todeliver medication 100 and then withdraw the tissue penetrating memberfrom the intestinal wall. In various embodiments, actuating mechanism 60can comprise a spring loaded mechanism which is configured to bereleased by release element 70. Suitable springs 80 can include bothcoil (including conical shaped springs) and leaf springs with otherspring structures also contemplated. In particular embodiments, spring80 can be substantially cone-shaped to reduce the length of the springin the compressed state even to the point where the compressed length ofthe spring is about the thickness of several coils (e.g., two or three)or only one coil.

In particular embodiments actuating mechanism 60 can comprise a spring80, a first motion converter 90, and a second motion converter 94 and atrack member 98 as is shown in the embodiments of FIGS. 2, 4 and 8 a-8c. The release element 70 is coupled to spring 80 to retain the springin a compressed state such that degradation of the release elementreleases the spring. Spring 80 may be coupled to release element 70 by alatch or other connecting element 81. First motion converter 90 isconfigured to convert motion of spring 80 to advance and withdraw thetissue penetrating member 40 in and out of the intestinal wall or othertissue. The second motion converter 94 is configured to convert motionof the spring 80 to advance the delivery member 50 into the tissuepenetrating member lumen 44. Motion converters 90 and 94 are pushed bythe spring and ride along a rod or other track member 98 which fits intoa track member lumen 99 of converter 90. The track member 98 serves toguide the path of the converters 90. Converters 90 and 94 engage thetissue penetrating member 40 and/or delivery member 50 (directly orindirectly) to produce the desired motion. They have a shape and othercharacteristics configured to convert motion of the spring 80 along itslongitudinal axis into orthogonal motion of the tissue penetratingmember 40 and/or delivery member 50 though conversion in otherdirections is also contemplated. The motion converters can have a wedge,trapezoidal or curved shape with other shapes also contemplated. Inparticular embodiments, the first motion converter 90 can have atrapezoidal shape 90 t and include a slot 93 which engages a pin 41 onthe tissue penetrating member that rides in the slot as is shown in theembodiments of FIGS. 2, 3 and 4. Slot 93 can also have a trapezoidalshape 93 t that mirrors or otherwise corresponds to the overall shape ofconverter 90. Slot 93 serves to push the tissue penetrating member 40during the upslope portion 91 of the trapezoid and then pull it backduring the down slope portion 92. In one variation, one or both of themotion converters 90 and 94 can comprise a cam or cam like device (notshown). The cam can be turned by spring 80 so as to engage the tissuepenetrating and/or delivery members 40 and 50. One or more components ofmechanism 60 (as well as other components of device 10) including motionconverters 90 and 94 can be fabricated using various MEMS-based methodsknown in the art so as to allow for selected amounts of miniaturizationto fit within capsule 10. Also as is described herein, they can beformed from various biodegradable materials known in the art.

In other variations, the actuating mechanism 60 can also comprise anelectro-mechanical device/mechanism such as a solenoid, or apiezoelectric device. In one embodiment, a piezoelectric device used inmechanism 60 can comprise a shaped piezoelectric element which has anon-deployed and deployed state. This element can be configured to gointo the deployed state upon the application of a voltage and thenreturn to the non-deployed state upon the removal of the voltage. Thisand related embodiments allow for a reciprocating motion of theactuating mechanism 60 so as to both advance the tissue penetratingmember and then withdraw it. The voltage for the piezoelectric elementcan be obtained generated using a battery or a piezoelectric basedenergy converter which generates voltage by mechanical deformation suchas that which occurs from compression of the capsule 20 by a peristalticcontraction of the small intestine around the capsule. Furtherdescription of piezoelectric based energy converters is found in U.S.patent application Ser. No. 12/556,524 which is fully incorporated byreference herein for all purposes. In one embodiment, deployment oftissue penetrating members 40 can in fact be triggered from aperistaltic contraction of the small intestine which provides themechanical energy for generating voltage for the piezoelectric element.

Release element 70 will typically be coupled to the actuating mechanism60 and/or a spring coupled to the actuating mechanism; however, otherconfigurations are also contemplated.

In preferred embodiments, release element 70 is coupled to a spring 80positioned within capsule 20 so as to retain the spring in a compressedstate 85 as shown in the embodiment of FIG. 2. Degradation of therelease element 70 releases spring 80 to actuate actuation mechanism 60.Accordingly, release element 70 can thus function as an actuator 70 a(actuator 70 may also include spring 80 and other elements of mechanism60). As is explained further below, release element 70/actuator 70 a hasa first configuration where the therapeutic agent preparation 100 iscontained within capsule 20 and a second configuration where thetherapeutic agent preparation is advanced from the capsule into the wallof the small intestine or other luminal wall in the intestinal tract.

In many embodiments, release element 70 comprises a material configuredto degrade upon exposure to chemical conditions in the small or largeintestine such as pH. Typically, release element 70 is configured todegrade upon exposure to a selected pH in the small intestine, e.g.,7.0, 7.1, 7.2, 7.3, 7.4, 7.5, 7.6 8.0 or greater. The release elementcan also be configured to degrade within a particular range of pH suchas, e.g., 7.0 to 7.5. In particular embodiments, the pH at which releaseelement 70 degrades (defined herein as the degradation pH) can beselected for the particular drug to be delivered so as to release thedrug at a location in small intestine which corresponds to the selectedpH. Further, for embodiments of device 10 having multiple medications100, the device can include a first release element 70 (coupled to anactuating mechanism for delivering a first drug) configured to degradeat first pH and a second release element 70 (coupled to an actuatingmechanism for delivering a second drug) configured to degrade at asecond pH (with additional numbers of release elements contemplated forvarying number of drugs).

Release element 70 can also be configured to degrade in response toother conditions in the small intestine (or other GI location). Inparticular embodiments, the release element 70 can be configured todegrade in response to particular chemical conditions in the fluids inthe small intestine such as those which occur after ingestion of a meal(e.g., a meal containing fats, starches or proteins). In this way, therelease of medication 100 can be substantially synchronized or otherwisetimed with the digestion of a meal. Such embodiments are particularlyuseful for the delivery of medication to control levels of blood glucose(e.g., insulin), serum cholesterol and serum triglycerides.

Various approaches are contemplated for biodegradation of releaseelement 70. In particular embodiments, biodegradation of release element70 from one or more conditions in the small intestine (or other locationin the GI tract) can be achieved by one or more of the following: i)selection of the materials for the release element, ii) the amount ofcross linking of those materials; and iii) the thickness and otherdimensions of the release element. Lesser amounts of cross linking andor thinner dimensions can increase the rate of degradation and visaversa. Suitable materials for the release element can comprisebiodegradable materials such as various enteric materials which areconfigured to degrade upon exposure to the higher pH in the intestines.Suitable enteric materials include, but are not limited to, thefollowing: cellulose acetate phthalate, cellulose acetate trimellitate,hydroxypropyl methylcellulose phthalate, polyvinyl acetate phthalate,carboxymethylethylcellulose, co-polymerized methacrylic acid/methacrylicacid methyl esters as well as other enteric materials known in the art.The selected enteric materials can be copolymerized or otherwisecombined with one or more other polymers to obtain a number of otherparticular material properties in addition to biodegradation. Suchproperties can include without limitation stiffness, strength,flexibility and hardness.

In alternative embodiments, the release element 70 can comprise a filmor plug 70 p that fits over or otherwise blocks guide tubes 30 andretains the tissue penetrating member 40 inside the guide tube. In theseand related embodiments, tissue penetrating member 40 is coupled to aspring loaded actuating mechanism such that when the release element isdegraded sufficiently, it releases the tissue penetrating member whichthen springs out of the guide tube to penetrate into the intestinalwall. In still other embodiments, release element 70 can be shaped tofunction as a latch which holds the tissue penetrating member 40 inplace. In these and related embodiments, the release element can belocated on the exterior or the interior of capsule 20. In the lattercase, capsule 20 and/or guide tubes 30 can be configured to allow forthe ingress of intestinal fluids into the capsule interior to allow forthe degradation of the release element.

In some embodiments, actuating mechanism 60 can be actuated by means ofa sensor 67, such as a pH sensor 68 or other chemical sensor whichdetects the presence of the capsule in the small intestine. Sensor 67can then send a signal to actuating mechanism 60 or to an electroniccontroller 29 c coupled to actuating mechanism 60 to actuate themechanism. Embodiments of a pH sensor 68 can comprise an electrode-basedsensor or it can be a mechanically-based sensor such as a polymer whichshrinks or expands upon exposure to a selected pH or other chemicalconditions in the small intestine. In related embodiments, anexpandable/contractible sensor 67 can also comprise the actuatingmechanism 60 itself by using the mechanical motion from the expansion orcontraction of the sensor.

According to another embodiment for detecting that the device in thesmall intestine (or other location in the GI tract), sensor 67 cancomprise pressure/force sensor such as strain gauge for detecting thenumber of peristaltic contractions that capsule 20 is being subject towithin a particular location in the intestinal tract (in suchembodiments capsule 20 is desirably sized to be gripped by the smallintestine during a peristaltic contraction). Different locations withinthe GI tract have different number of peristaltic contractions. Thesmall intestine has between 12 to 9 contractions per minute with thefrequency decreasing down the length of the intestine. Thus, accordingto one or more embodiments, detection of the number of peristalticcontractions can be used to not only determine if capsule 20 is in thesmall intestine, but the relative location within the intestine as well.In use, these and related embodiments allow for release of medication100 at a particular location in the small intestine.

As an alternative or supplement to internally activated drug delivery(e.g., using a release element and/or sensor), in some embodiments, theuser may externally activate the actuating mechanism 60 to delivermedication 100 by means of RF, magnetic or other wireless signalingmeans known in the art. In these and related embodiments, the user canuse a handheld communication device 13 (e.g., a hand held RF device suchas a cell phone) as is shown in the embodiment of FIG. 1b , to send areceive signals 17 from device 10. In such embodiments, swallowabledevice may include a transmitter 28 such as an RF transceiver chip orother like communication device/circuitry. Handheld device 13 may notonly includes signaling means, but also means for informing the userwhen device 10 is in the small intestine or other location in the GItract. The later embodiment can be implemented through the use of logicresources 29 (e.g., a processor 29) coupled to transmitter 28 to signalto detect and singe to the user when the device is in the smallintestine or other location (e.g., by signaling an input from thesensor). Logic resources 29 may include a controller 29 c (either inhardware or software) to control one or more aspects of the process. Thesame handheld device can also be configured to alert the user whenactuating mechanism 60 has been activated and the selected medication100 delivered (e.g., using processor 29 and transmitter 28). In thisway, the user is provided confirmation that medication 100 has beendelivered. This allows the user to take other appropriatedrugs/therapeutic agents as well as make other related decisions (e.g.,for diabetics to eat a meal or not and what foods should be eaten). Thehandheld device can also be configured to send a signal to swallowabledevice 10 to over-ride actuating mechanism 60 and so prevent delay oraccelerate the delivery of medication 100. In use, such embodimentsallow the user to intervene to prevent, delay or accelerate the deliveryof medication, based upon other symptoms and/or patient actions (e.g.,eating a meal, deciding to go to sleep, exercise etc). The user may alsoexternally activate actuating mechanism 60 at a selected time periodafter swallowing the capsule. The time period can be correlated to atypical transit time or range of transit times for food moving throughthe user's GI tract to a particular location in the tract such as thesmall intestine.

In particular embodiments, the capsule 20 can include seams 22 ofbiodegradable material which controllably degrade to produce capsulepieces 23 of a selectable size and shape to facilitate passage throughthe GI tract as is shown in the embodiment of FIGS. 10a and 10b . Seams22 can also include pores or other openings 22 p for ingress of fluidsinto the seam to accelerate biodegradation as is shown in the embodimentof FIG. 10. Other means for accelerating biodegradation of seams 22 caninclude pre-stressing the seam and/or including perforations 22 f in theseam as is also shown in the embodiment of FIG. 10. In still otherembodiments, seam 22 can be constructed of materials and/or have astructure which is readily degraded by absorption of ultrasound energy,e.g. high frequency ultrasound (HIFU), allowing the capsule to bedegraded into smaller pieces using externally or endoscopically (orother minimally invasive method) administered ultrasound.

Suitable materials for seams 22 can include one or more biodegradablematerials described herein such as PGLA, glycolic acid etc. Seams 22 canbe attached to capsule body 20 using various joining methods known inthe polymer arts such as molding, hot melt junctions, etc. Additionallyfor embodiments of capsule 20 which are also fabricated frombiodegradable materials, faster biodegradation of seam 22 can beachieved by one or more of the following: i) fabricating the seam from afaster biodegrading material, ii) pre-stressing the seam, or iii)perforating the seam. The concept of using biodegradable seams 22 toproduce controlled degradation of a swallowable device in the GI tractcan also be applied to other swallowable devices such as swallowablecameras (or other swallowable imaging device) to facilitate passagethrough the GI tract and reduce the likelihood of such a device becomingstuck in the GI tract. Accordingly, embodiments of biodegradable seam 22can be adapted for swallowable imaging and other swallowable devices.

Another aspect of the invention provides methods for the delivery ofdrugs and other therapeutic agents (in the form of medication 100) intothe walls of the GI tract using one or more embodiments of swallowabledrug delivery device 10. An exemplary embodiment of such a method willnow be described. The described embodiment of drug delivery occurs inthe small intestine SI. However, it should be appreciated that this isexemplary and that embodiments of the invention can be used fordelivering drug in a number of locations in the GI tract including thestomach and the large intestine. For ease of discussion, the swallowabledrug delivery device 10 will sometimes be referred to herein as acapsule. As described above, in various embodiments device 10 may bepackaged as a kit 11 within sealed packaging 12 that includes device 10and a set of instructions for use 15. If the patient is using a handhelddevice 13, the patient may instructed to enter data into device 13either manually or via a bar code 18 (or other identifying indicia 18)located on the instructions 15 or packaging 12. If a bar code is used,the patient would scan the bar code using a bar code reader 19 on device13. After opening packaging 12, reading the instructions 15 and enteringany required data, the patient swallows an embodiment of the swallowabledrug delivery device 10. Depending upon the drug, the patient may takethe device 10 in conjunction with a meal (before, during or after) or aphysiological measurement such as a blood glucose measurement. Capsule20 is sized to pass through the GI tract and travels through thepatient's stomach S and into the small intestine SI through peristalticaction as is shown in the embodiment of FIG. 11. Once in the smallintestine, the release element 70 is degraded by the basic pH in thesmall intestine (or other chemical or physical condition unique to thesmall intestine) so as to actuate the actuating mechanism 60 and delivermedication 100 into the wall of the small intestine SI according to oneor more embodiments of the invention. For embodiments including a hollowneedle or other hollow tissue penetrating member 40, medication deliveryis effectuated by using the actuating mechanism 60 to advance the needle40 a selected distance into the mucosa of the intestinal wall IS, andthen the medication is injected through the needle lumen 40 byadvancement of the delivery member 50. The delivery member 50 iswithdrawn and the needle 40 is then withdrawn back within the body ofthe capsule (e.g. by recoil of the spring) detaching from the intestinalwall. For embodiments of device 10 having multiple needles, a second orthird needle 42, 43 can also be used to deliver additional doses of thesame drug or separate drugs 101. Needle advancement can be donesubstantially simultaneously or in sequence. In preferred embodimentsthat use multiple needles, needle advancement can be done substantiallysimultaneously so as to anchor device 10 in the small intestine duringdrug delivery.

After medication delivery, device 10 then passes through the intestinaltract including the large intestine LI and is ultimately excreted. Forembodiments of the capsule 20 having biodegradable seams 22 or otherbiodegradable portions, the capsule is degraded in the intestinal tractinto smaller pieces to facilitate passage through and excretion from theintestinal tract as is shown in the embodiments of FIGS. 9a and 9b . Inparticular embodiments having biodegradable tissue penetratingneedles/members 40, should the needle get stuck in the intestinal wall,the needle biodegrades releasing the capsule 20 from the wall.

For embodiments of device 10 including a sensor 67, actuation ofmechanism 60 can be effectuated by the sensor sending a signal toactuating mechanism 60 and/or a processor 29/controller 29 c coupled tothe actuating mechanism. For embodiments of device 10 including externalactuation capability, the user may externally activate actuatingmechanism 60 at a selected time period after swallowing the capsule. Thetime period can be correlated to a typical transit time or range oftransit times for food moving through the user's GI tract to aparticular location in the tract such as the small intestine.

One or more embodiments of the above methods can be used for thedelivery of preparations 100 containing therapeutically effectiveamounts of a variety of drugs and other therapeutic agents 101 to treata variety of diseases and conditions. These include a number of largemolecule peptides and proteins which would otherwise require injectiondue to chemical breakdown in the stomach, e.g., growth hormone,parathyroid hormone, insulin, interferons and other like compounds.Suitable drugs and other therapeutic agents which can be delivered byembodiments of the invention include various chemotherapeutic agents(e.g., interferon), antibiotics, antivirals, insulin and relatedcompounds, glucagon like peptides (e.g., GLP-1, exenatide), parathyroidhormones, growth hormones (e.g., IFG and other growth factors),anti-seizure agents (e.g., Furosimide), anti-migraine medication(sumatriptan), immune suppression agents (e.g., cyclosporine) andanti-parasitic agents such as various anti-malarial agents. The dosageof the particular drug can be titrated for the patient's weight, age orother parameter. Also the drug 101 to achieve a desired or therapeuticeffect (e.g., insulin for blood glucose regulation, Furosimide foranti-seizure) can be less than the amount required should the drug havebeen delivered by conventional oral delivery (e.g., a swallowable pillthat is digested in the stomach and absorbed through the wall of thesmall intestine). This is due to the fact that there is no degradationof the drug by acid and other digestive fluids in the stomach and thefact that all, as opposed to only a portion of the drug is deliveredinto the wall of the small intestine (or other lumen in the intestinaltract, e.g., large intestine, stomach, etc.). Depending upon the drug101, the dose 102 delivered in preparation 100 can be in the range from100 to 5% of a dose delivered by conventional oral delivery means toachieve a desired therapeutic effect (e.g., blood glucose regulation,seizure regulation, etc.) with even lower amounts contemplated. Theparticular dose reduction can be titrated based upon the particulardrug, the condition to be treated, and the patient's weight, age andcondition. For some drugs (with known levels of degradation in theintestinal tract) a standard dose reduction can be employed (e.g., 10 to20%). Larger amounts of dose reduction can be used for drugs which aremore prone to degradation and poor absorption. In this way, thepotential toxicity and other side effects (e.g., gastric cramping,irritable bowel, hemorrhage, etc.) of a particular drug or drugsdelivered by device 10 can be reduced because the ingested dose islowered. This in turn, improves patient compliance because the patienthas reduction both in the severity and incidence of side effects.Additional benefits of embodiments employing dose reduction of drug 101include a reduced likelihood for the patient to develop a tolerance tothe drug (requiring higher doses) and, in the case of antibiotics, forthe patient to develop resistant strains of bacteria. Also, other levelsof dose reduction can be achieved for patients undergoing gastric bypassoperations and other procedures in which sections of the small intestinehave been removed or its working (e.g., digestive) length effectivelyshortened.

In addition to delivery of a single drug, embodiments of swallowabledrug delivery device 10 and methods of their use can be used to delivera plurality of drugs for the treatment of multiple conditions or for thetreatment of a particular condition (e.g., protease inhibitors fortreatment HIV AIDS). In use, such embodiments allow a patient to forgothe necessity of having to take multiple medications for a particularcondition or conditions. Also, they provide a means for facilitatingthat a regimen of two or more drugs is delivered and absorbed into thesmall intestine and thus, the blood stream, at about the same time. Dueto difference in chemical makeup, molecular weight, etc, drugs can beabsorbed through the intestinal wall at different rates, resulting indifferent pharmacokinetic distribution curves. Embodiments of theinvention address this issue by injecting the desired drug mixtures atsubstantially the same time. This in turn, improves the pharmacokineticsand thus the efficacy of the selected mixture of drugs. Additionally,eliminating the need to take multiple drugs is particularly beneficialto patients who have one or more long term chronic conditions includingthose who have impaired cognitive or physical abilities.

In various applications, embodiments of the above methods can be used todeliver preparations 100 including drugs and therapeutic agents 101 toprovide treatment for a number of medical conditions and diseases. Themedical conditions and diseases which can be treated with embodiments ofthe invention can include without limitation: cancer, hormonalconditions (e.g., hypo/hyper thyroid, growth hormone conditions),osteoporosis, high blood pressure, elevated cholesterol andtriglyceride, diabetes and other glucose regulation disorders, infection(local or septicemia), epilepsy and other seizure disorders,osteoporosis, coronary arrhythmia's (both atrial and ventricular),coronary ischemia anemia or other like condition. Still other conditionsand diseases are also contemplated.

In many embodiments, the treatment of the particular disease orcondition can be performed without the need for injecting the drug orother therapeutic agent (or other non-oral form of delivery such assuppositories) but instead, relying solely on the therapeutic agent(s)that is delivered into the wall of the small intestine or other portionof the GI tract. For example, diabetes or another glucose regulationdisorder can be treated (e.g., by controlling blood glucose levels)solely through the use of insulin that is delivered into the wall of thesmall intestine without the need for the patient to ever inject insulin.Similarly, the patient need not take conventional oral forms of a drugor other therapeutic agent, but again rely solely on delivery into thewall of the small intestine using embodiments of the swallowablecapsule. In other embodiments, the therapeutic agent(s) delivered intothe wall of the small intestine can be delivered in conjunction with aninjected dose of the agent(s). For example, the patient may take a dailydose of insulin or compound for blood glucose regulation using theembodiments of the swallowable capsule, but only need take an injecteddose every several days or when the patient's condition requires it(e.g., hyperglycemia). The same is true for therapeutic agents that aretraditionally delivered in oral form (e.g., the patient can take theswallowable capsule and take the conventional oral form of the agent asneeded). The dosages delivered in such embodiments (e.g., the swallowedand injected dose) can be titrated as needed (e.g., using standard doseresponse curve and other pharmacokinetic methods can be used todetermine the appropriate dosages). Also, for embodiments usingtherapeutic agents that can be delivered by conventional oral means, thedose delivered using embodiments of the swallowable capsule can betitrated below the dosage normally given for oral delivery of the agentsince there is little or no degradation of the agent within the stomachor other portion of the intestinal tract (herein again standard doseresponse curve and other pharmacokinetic methods can be applied).

Various groups of embodiments of preparation 100 containing one or moredrugs or other therapeutic agents 101 for the treatment of variousdiseases and conditions will now be described with references todosages. It should be appreciated that these embodiments, including theparticular therapeutic agents and the respective dosages are exemplaryand the preparation 100 can comprise a number of other therapeuticagents described herein (as well as those known in the art) that areconfigured for delivery into a luminal wall in the intestinal tract(e.g., the small intestinal wall) using various embodiments of device10. The dosages can be larger or smaller than those described and can beadjusted using one or more methods described herein or known in the art.In one group of embodiments, therapeutic agent preparation 100 cancomprise a therapeutically effective dose of insulin for the treatmentof diabetes and other glucose regulation disorders. The insulin can behuman or synthetically derived as is known in the art. In oneembodiment, preparation 100 can contain a therapeutically effectiveamount of insulin in the range of about 1-10 units (one unit being thebiological equivalent of about 45.5 .mu.g of pure crystalline insulin),with particular ranges of 2-4, 3-9, 4-9, 5-8 or 6-7. The amount ofinsulin in the preparation can be titrated based upon one or more of thefollowing factors (herein, “glucose control titration factors”): i) thepatient's condition (e.g., type 1 vs. type II diabetes; ii) the patientsprevious overall level of glycemic control; iii) the patient's weight;iv) the patient's age; v) the frequency of dosage (e.g., once vs.multiple times a day); vi) time of day (e.g., morning vs. evening); vii)particular meal (breakfast vs. dinner); vii) content/glycemic index of aparticular meal (e.g., high fat/lipid and sugar content (e.g., foodscausing a rapid rise in blood sugar) vs.

low fat and sugar content; and viii) content of the patient's overalldiet (e.g., amount of sugars and other carbohydrates, lipids and proteinconsumed daily).

In another group of embodiments, therapeutic agent preparation 100 cancomprise a therapeutically effective dose of one or more incretins forthe treatment of diabetes and other glucose regulation disorders. Suchincretins can include Glucacon like peptides 1 (GLP-1) and theiranalogues, and Gastric inhibitory peptide (GIP). Suitable GLP-1analogues include exenatide, liraglutide, albiglutide and taspoglutideas well as their analogues, derivatives and other functionalequivalents. In one embodiment preparation 100 can contain atherapeutically effective amount of exenatide in the range of about 1-10.mu.g, with particular ranges of 2-4, 4-6, 4-8 and 8-10 .mu.grespectively. In another embodiment, preparation 100 can contain atherapeutically effective amount of liraglutide in the range of about1-2 mg (milligrams), with particular ranges of 1.0 to 1.4, 1.2 to 1.6and 1.2 to 1.8 mg respectively. One or more of the glucose controltitration factors can be applied to titrate the dose ranges forexenatide, liraglutide or other GLP-1 analogue or incretin.

In yet another group of embodiments, therapeutic agent preparation 100can comprise a combination of therapeutic agents for the treatment ofdiabetes and other glucose regulation disorders. Embodiments of such acombination can include therapeutically effective doses of incretin andbiguanide compounds. The incretin can comprise one or more GLP-1analogues described herein, such as exenatide and the biguanide cancomprise metformin (e.g., that available under the Trademark ofGLUCOPHAGE® manufactured by Merck Sante S.A.S.) and its analogue,derivatives and other functional equivalents. In one embodiment,preparation 100 can comprise a combination of a therapeuticallyeffective amount of exenatide in the range of about 1-10 .mu.g and atherapeutically effective amount of metformin in a range of about 1 to 3grams. Smaller and larger ranges are also contemplated with one or moreof the glucose control titration factors used to titrate the respectivedose of exenatide (or other incretin) and metformin or other biguanide.Additionally, the dosages of the exenatide or other incretin andmetformin or other biguanide can be matched to improved level of glucosecontrol for the patient (e.g., maintenance of blood glucose withinnormal physiological levels and/or a reduction in the incidence andseverity of instances of hyperglycemia and/or hypoglycemia) for extendedperiods of time ranges from hours (e.g., 12) to a day to multiple days,with still longer periods contemplated. Matching of dosages can also beachieved by use of the glucose control regulation factors as well asmonitoring of the patient's blood glucose for extended periods usingglycosylated hemoglobin (known as hemoglobin A1c, HbA1c, A1C, or Hb1c)and other analytes and measurements correlative to long term averageblood glucose levels.

In still yet another group of embodiments, therapeutic agent preparation100 can comprise a therapeutically effective dose of growth hormone forthe treatment of one or more growth disorders, as well as wound healing.In one embodiment, preparation 100 can contain a therapeuticallyeffective amount of growth hormone in the range of about 0.1-4 mg, withparticular ranges of 0.1-1, 1-4, 1-2 and 2-4, with still larger rangescontemplated. The particular dose can be titrated based on one or moreof the following: i) the particular condition to be treated and itsseverity (e.g., stunted growth, vs. wound healing); ii) the patient'sweight; iii) the patient's age; and iv) the frequency of dosage (e.g.,daily vs. twice daily).

In still yet another group of embodiments, therapeutic agent preparation100 can comprise a therapeutically effective dose of parathyroid hormonefor the treatment osteoporosis or a thyroid disorder. In one embodiment,preparation 100 can contain a therapeutically effective amount ofparathyroid hormone in the range of about 1-40 .mu.g, with particularranges of 10-20, 20-30, 30-40 and 10-40 .mu.g, with still larger rangescontemplated. The particular dose can be titrated based on one or moreof the following: i) the particular condition to be treated and itsseverity (e.g., the degree of osteoporosis as determined by bone densitymeasurements); ii) the patient's weight; iii) the patient's age; and iv)the frequency of dosage (e.g., daily vs. twice daily).

Drug delivery compositions and components of known drug delivery systemsmay be employed and/or modified for use in some embodiments of theinventions described herein. For example, microneedles and othermicrostructures used for delivery of drugs through the skin surface withdrug patches may be modified and included within the capsules describedherein and used to instead deliver a drug into a lumen wall of thegastrointestinal tract. Suitable polymer microneedle structures may becommercially available from Corium of California, such as the MicroCor™micro delivery system technology. Other components of the MicroCor™patch delivery systems, including drug formulations or components, mayalso be incorporated into the capsules described herein. Alternatively,a variety of providers are commercially available to formulatecombinations of polymers or other drug-delivery matrices with selecteddrugs and other drug preparation components so as to produce desiredshapes (such as the releasable tissue-penetrating shapes describedherein) having desiragle drug release characteristics. Such providersmay, for example, include Corium, SurModics of Minnesota, BioSensorsInternational of Singapore, or the like.

The foregoing description of various embodiments of the invention hasbeen presented for purposes of illustration and description. It is notintended to limit the invention to the precise forms disclosed. Manymodifications, variations and refinements will be apparent topractitioners skilled in the art. For example, embodiments of the devicecan be sized and otherwise adapted for various pediatric and neonatalapplications as well as various veterinary applications. Also thoseskilled in the art will recognize, or be able to ascertain using no morethan routine experimentation, numerous equivalents to the specificdevices and methods described herein. Such equivalents are considered tobe within the scope of the present invention and are covered by theappended claims below.

Elements, characteristics, or acts from one embodiment can be readilyrecombined or substituted with one or more elements, characteristics oracts from other embodiments to form numerous additional embodimentswithin the scope of the invention. Moreover, elements that are shown ordescribed as being combined with other elements, can, in variousembodiments, exist as standalone elements. Hence, the scope of thepresent invention is not limited to the specifics of the describedembodiments, but is instead limited solely by the appended claims.

1. A therapeutic agent preparation for delivery into a lumen of anintestinal tract, the lumen having a lumen wall, the preparationcomprising a therapeutically effective dose of at least one therapeuticagent; wherein the preparation is configured to be contained in aswallowable capsule and operably coupled to an actuator having a firstconfiguration and a second configuration, the preparation beingcontained within the capsule in the first configuration and advanced outof the capsule and into the lumen wall in the second configuration so asto deliver the therapeutic agent into the lumen wall.
 2. The preparationof claim 1, wherein the lumen is a stomach and the preparation isconfigured to degrade within wall of the stomach.
 3. The preparation ofclaim 1, wherein the preparation comprises at least one pharmaceuticalexcipient.
 4. The preparation of claim 1, wherein the preparation isconfigured to have a selectable surface area to volume ratio to achievea selectable rate of release of the therapeutic agent in the lumen wall.5. The preparation of claim 1 wherein an amount of the therapeutic agentwithin the preparation to produce a desired therapeutic effect is lessthan an amount to produce a corresponding effect if the agent was orallydelivered without containment in the swallowable enclosure.
 6. Thepreparation of claim 1, wherein the preparation is configured to bedelivered within a lumen of a tissue penetrating member.
 7. Thepreparation of claim 1, wherein at least a portion of the preparation isshaped as a tissue penetrating member advanceable into the lumen wall,the tissue penetrating member having a pointed tip.
 8. The preparationof claim 1, wherein the therapeutic agent comprises a therapeuticallyeffective dose of insulin for the treatment of diabetes or a glucoseregulation disorder.
 9. The preparation of claim 8, wherein the dose ofinsulin is in a range from about 4 to 9 units of insulin.
 10. Thepreparation of claim 1, wherein the therapeutic agent comprises atherapeutically effective dose of an incretin for the treatment ofdiabetes or a glucose regulation disorder.
 11. The preparation of claim10, wherein the incretin comprises a glucagon like peptide-1 (GLP-1), aGLP-1 analogue, exenatide, liraglutide, albiglutide, taspoglutide or agastric inhibitory polypeptide (GIP).
 12. The preparation of claim 11,wherein the incretin comprises exenatide and wherein the therapeuticagent comprises a therapeutically effective dose of exenatide, the dosebeing in a range from about 1 to 10 μg.
 13. The preparation of claim 11,wherein the incretin comprises liraglutide and wherein the therapeuticagent comprises a therapeutically effective dose of exenatide, the dosebeing in a range from about 1 to 2 mg.
 14. The preparation of claim 1,wherein the therapeutic agent comprises a combination of therapeuticagents for the treatment of diabetes or a glucose regulation disorder.15. The preparation of claim 14, wherein the combination comprises atherapeutically effective dose of an incretin and a therapeuticallyeffective dose of a biguanide.
 16. The preparation of claim 15, whereinthe incretin comprises exenatide and the biguanide comprises metformin.17. The preparation of claim 15, wherein the doses of the incretin andthe biguanide are matched to produce an improved level of blood glucosecontrol for an extended period.
 18. The preparation of claim 1, whereinthe therapeutic agent comprises a therapeutically effective dose ofgrowth hormone.
 19. The preparation of claim 1, wherein the therapeuticagent comprises a therapeutically effective dose of parathyroid hormonefor the treatment of osteoporosis or a thyroid disorder.
 20. Thepreparation of claim 1, wherein the therapeutic agent comprises atherapeutically effective dose of a chemotherapeutic agent for treatmentof cancer.
 21. The preparation of claim 1, wherein the therapeutic agentcomprises a therapeutically effective dose of an antiviral compound. 22.A therapeutic preparation for delivery into a lumen of agastrointestinal tract, the lumen having a lumen wall, the preparationcomprising a therapeutically effective dose of at least one therapeuticagent, wherein at least a portion of the preparation is shaped as atissue penetrating member advanceable into the lumen wall, the tissuepenetrating member having a pointed tip.
 23. The preparation of claim22, wherein the preparation is configured to be contained in aswallowable enclosure and operably coupled to an actuator having a firstconfiguration and a second configuration, the preparation beingcontained within the enclosure in the first configuration and advancedout of the enclosure and into the lumen wall in the second configurationso as to deliver the therapeutic agent into the lumen wall.
 24. Thepreparation of claim 22, wherein the lumen is the a stomach and thepreparation is configured to degrade within the wall of the stomach. 25.The preparation of claim 22, wherein the preparation comprises at leastone pharmaceutical excipient.
 26. The preparation of claim 22, whereinthe preparation is configured to have a selectable surface area tovolume ratio to achieve a selectable rate of release of the therapeuticagent in the lumen wall.
 27. The preparation of claim 22, wherein anamount of the therapeutic agent within the preparation to produce adesired therapeutic effect is less than an amount to produce acorresponding effect if the agent was orally delivered withoutcontainment in the swallowable enclosure.
 28. The preparation of claim22, wherein the preparation is configured to be delivered within a lumenof a tissue penetrating member.
 29. The preparation of claim 22, whereinthe therapeutic agent comprises a therapeutically effective dose ofinsulin for the treatment of diabetes or a glucose regulation disorder.30. The preparation of claim 22, wherein the therapeutic agent comprisesa therapeutically effective dose of growth hormone, a therapeuticallyeffective dose of parathyroid hormone for the treatment of osteoporosisor a thyroid disorder, a therapeutically effective dose of achemotherapeutic agent for the treatment of cancer, or a therapeuticallyeffective dose of an antiviral compound.